Pretargeted Multimodal Tumor Imaging by Enzymatic Self-Immobilization Labeling and Bioorthogonal Reaction

Area of Science:

• Bioconjugation Chemistry
• Molecular Imaging
• Cancer Therapeutics

Background:

• Covalent cell membrane modification shows potential for tumor imaging and therapy.
• Current methods suffer from slow kinetics, poor cancer cell selectivity, off-target effects, and suboptimal in vivo efficacy.

Purpose of the Study:

• To develop a rapid and selective tumor cell membrane labeling strategy for in vivo applications.
• To enable pretargeted multimodality imaging and therapy by enriching bioorthogonal reporters on cancer cells.

Main Methods:

• Introduced E-SIM (Enzyme-triggered Self-Immobilization), utilizing an alkaline phosphatase (ALP)-responsive quinone methide (QM) precursor (P-TCO) with a trans-cyclooctene (TCO) group.
• Employed proximity labeling for rapid, high-density conjugation of TCO handles onto tumor cell membranes in vivo.
• Utilized fast bioorthogonal reaction between TCO handles and tetrazine (Tz)-bearing reporters for reporter enrichment.

Main Results:

• Demonstrated E-SIM enables rapid and selective labeling of tumor cell membranes with TCO handles in vivo.
• Achieved efficient enrichment of various sized Tz-bearing reporters on labeled tumor cell membranes.
• Successfully applied E-SIM for pretargeted bioluminescence imaging of liver tumor metastases using Tz-modified Renilla luciferase, enabling sensitive detection and surgical guidance.

Conclusions:

• E-SIM is a robust strategy for precise in vivo tumor cell labeling in complex biological environments.
• The approach facilitates pretargeted enrichment of diverse reporters for multimodal tumor imaging and therapeutic applications.
• E-SIM enhances in vivo imaging sensitivity and accuracy, offering potential for improved cancer detection and treatment guidance.